All publications cited herein are incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Chronic pancreatitis (CP) is characterized by progressive and what is thought to be irreversible damage to the pancreas, with end result of endocrine and exocrine insufficiency. CP histologic features include chronic inflammation, fibrosis, acinar cell atrophy and distorted and/or blocked ducts. The management of CP is challenging with focus on the management of complications, and most patients remain symptomatic despite limited supportive therapy. Currently, there are no effective methods to limit progression or reverse this syndrome. Recurrent AP or pancreatic insults lead to necroinflammation and are linked to the development of pancreatic fibrosis (the necrosis-fibrosis concept). Recent in vitro and in vivo studies demonstrate the central role of activated pancreatic stellate cells (PSCs) in CP-associated fibrogenesis by regulating the synthesis and degradation of extracellular matrix proteins. PSCs are activated by many factors such as toxic factors associated with pancreatitis (for example, ethanol) and/or by cytokines released from injured acinar cells and/or pancreas-infiltrating leukocytes (such as macrophages and neutrophils).
Macrophages are innate immune cells, which are for simplicity divided into two spectra of major types based on Siamon Gordon's scheme: (1) classically activated macrophages (M1), induced by interferon gamma (IFNγ) and/or lipopolysaccharide, characterized by the production of reactive oxygen and nitrogen species and thought to play a critical role in host defense and antitumour immunity; and (2) alternatively activated macrophages (AAMs, M2), on exposure to IL-4/IL-13, are characterized by cell surface expression of scavenger receptors CD206. AAMs play key roles in dampening inflammation, promote wound-healing, fibrosis and tumorigenesis. Recent studies highlighted the function of macrophages as master regulators of fibrosis. Distinct macrophage populations contribute important activities towards the initiation, maintenance and resolution phase of fibrosis. Macrophages have been observed in dose proximity to PSCs in human pancreatic fibrosis, and their presence observed in rat model of CP, although not well defined, their potential role in CP has been suggested. Thus, the mechanism(s) by which crosstalk between activated stellate cells and macrophages trigger and sustain the fibrotic process during CP is not known. Delineating immune responses involved in the fibrotic processes will improve our understanding of disease pathogenesis and allow for designing novel therapeutics that can either treat and/or reverse the disease. Our study investigates and identifies macrophage characteristics and function in CP.
Herein, the inventors demonstrate that progression to CP is associated with alternative activation of macrophages and show an important role for the IL-4/IL-13 pathway in a crosstalk between macrophages and PSCs using in vivo and in vitro animal studies as well as ex vivo human primary cells. Notably, blocking IL-4/IL-13 using a peptide antagonist we show a therapeutic effect in established experimental CP and proof-of-concept therapeutic ex vivo effect using human samples. These studies are likely to offer potential benefit in a disease for which currently no active therapeutic agent exists and as such the disease is deemed progressive and irreversible.